Low frequency K103N mutations are associated with poor virological response to NNRTI based therapy

Gilian Hunt and co-workers showed findings from an observational epidemiological study comparing HIV-positive women from Johannesburg clinics exposed (n=94) and unexposed (n=60) to single-dose nevirapine (sdNVP) for mother to child transmission prophylaxis 18-36 months earlier.

In this study, pre-treatment samples were tested for K103N mutations using an allele-specific real time PCR (AS-PCR). Population sequencing was performed on samples from women who did not achieve a viral load <50 copies/mL or did not sustain viral suppression to 78 weeks.

All women received South African first-line regimens (d4T/3TC plus either nevirapine or efavirenz).

The investigators found K103N mutations detected by AS-PCR in 10.6% samples from the sdNVP exposed and 15% reportedly unexposed women. 57.8% of women with baseline resistance had an inadequate virological response. Only 36.7% of the 30 women across both groups with an inadequate virological response had K103N mutations detected pre-treatment.

The investigators then performed an analysis of other minority mutant populations in the earliest failing samples and found different mutation patterns between the two groups of women. K103N was more frequent among the exposed women (9/18, 50%) than the unexposed women (3/12, 33%) and M184V/I was more frequent among the unexposed (9/12, 75%) than the exposed (6/18, 33%). In both groups most women had at least one NNRTI mutation 13/18 (72%) exposed women and 10/12 (83%) unexposed women in their failing sample.

The investigators concluded that in this study exposure to sdNVP was not associated with reduced likelihood of achieving undetectable viral load <50 copies/mL or with sustained response at 78 weeks.

However K103N mutations were strongly associated with compromised response. Most women were initially undetectable but this was not sustained and K103N mutations were associated with a >3-fold risk of viral rebound. They wrote: “The consequences of underlying resistance mutations were not apparent within the fist 6 months of therapy but clearly affected the durability of viral suppression after 6 months.”

They noted that despite comparable levels of K103N in both groups s/dNVP exposed women appeared to fail with K103N and unexposed M184V.

They suggested that possibly the K103N is archived in previously exposed women at undetectable levels. In unexposed women they suggest that M184 mutation, which is known to appear rapidly but results in a compromised virus, subsequently delays the development of other resistance related codons. 2These discrepancies in virus evolution between the two groups warrant further investigation.” they added.

Hunt G, Coovadia A, EJ Abrams et al. Low frequency K103N mutations are strongly associated with inadequate virological response to non-nucleoside reverse transcriptase inhibitor based therapy. XVII IHDRW 2008, Sitges. Abstract 120.